Adenosine Triphosphate and Adenosine Increase the Pulmonary Blood Flow to Postnatal Levels in Fetal Lambs

Abstract

ABSTRAa. We investigated the hypothesis that purine nucleotides may mediate the pulmonary vasodilation that occurs at birth in fetal lambs. We studied nine fetal lambs 3 d after placement of intravascular catheters, a flow transducer around the left pulmonary artery, and an inflatable vascular occluder around the ductus arteriosus. The pressure-flow relationship of left lung during a brief occlusion of the ductus arteriosus was studied as an index of pulmonary vascular resistance. We investigated the pulmonary vascular effects of adenosine, ATP, or saline (control) in doses of 0.01-2.50 pmol/kg/min infused into the right atrial line, and measured blood adenosine and ATP levels in samples from the pulmonary artery and left atrium. We also investigated the mechanism of pulmonary vascular effects of adenosine and ATP. Adenosine and ATP caused significant decreases in pulmonary vascular resistance and increases in pulmonary blood flow in doses of 0.08-2.5 pmol/kg/min. The pulmonary blood flow increased to levels seen in postnatal lambs at doses of 1.2 and 2.5 pmol/kg/min of adenosine and ATP. The baseline blood adenosine and ATP levels in fetus were 8 and 70% of levels in postnatal lambs. ATP concentrations increased to postnatal levels and adenosine levels increased to 20% of postnatal levels at infusion rates of 1.2 and 2.5 wmol/ kg/min. The pulmonary vasodilation caused by adenosine and ATP was attenuated by 8-phenyltheophylline and cibacron blue, respectively, but not by indomethacin. We conclude that adenosine and ATP are pulmonary vasodilators and increase the fetal pulmonary flow to postnatal levels in doses that increase their blood concentrations to I postnatal levels. The effects of adenosine and ATP are mediated by stimulation of PI and P2 purinergic receptors and are independent of prostacyclin synthesis. Purine nucleotides may be important mediators of pulmonary vasodilation that occurs in the perinatal lamb. The fetal lung undergoes significant changes at birth to prepare itself for the function of gas exchange during postnatal life. These changes include a rapid decrease in PVR and a 10-fold increase in pulmonary blood flow (I). The factors that decrease the PVR at birth include onset of ventilation (2) and exposure to higher oxygen tension (3, 4). Studies done in fetal lambs have shown that both factors have independent effects (2, 3) on fetal pulmonary vessels, although they appear to act in concert at birth. The pulmonary vasodilation caused by ventilation of fetal lamb's lungs can be blocked by indomethacin (5,6) and is accompanied by increased release of prostacyclin into pulmonary circulation (7). However, the increase in pulmonary flow in response to an increase in oxygen tension in the fetal lamb appears to be independent of prostaglandin synthesis ( 5 , 8).We previously reported (9, 10) that adenosine and ATP are pulmonary vasodilators in postnatal lambs and that they dilate the pulmonary vessels during hypoxia-induced pulmonary hypertension in lambs. We proposed the hypothesis that increased...

Decreased association of HSP90 impairs endothelial nitric oxide synthase in fetal lambs with persistent pulmonary hypertension

“…The plasma levels of ATP increased during exposure of fetal lambs to oxygen, alone or accompanied by lung distension (15,18). Infusion of ATP and its metabolites into fetal pulmonary artery reproduced the pulmonary vasodilation that occurs at birth in fetal lambs (19). Inhibition of ATP synthesis (16) or receptors for ATP and its metabolite adenosine (15,18) attenuated the birth-related pulmonary vasodilation in fetal lambs.…”

“…Control fetal lambs had blood gas tension measurements at the same time points. In addition, the fetal mean systemic and pulmonary arterial pressures were measured at the same time points with the appropriate pressure transducers (model PT 100, Grass Instruments) and physiograph (model 7D, Grass), as described previously (19). After 8 days of ductal constriction, the ewe was euthanized and laparotomy and hysterotomy incisions were quickly opened.…”

Cardiac purinergic signalling in health and disease

“…Several studies in animal models of pulmonary hypertension demonstrated the beneficial effects of ATP infusion in this setting [811][812][813][814][815]. Pulmonary hypertension is a serious problem in children with congenital heart defects.…”

Purinergic Signaling in the Airways

“…ATP and adenosine increase pulmonary blood flow in perinatal lamb via P1 and P2 receptors that are independent of prostacyclin synthesis (Konduri et al, 1992), later identified as A 2A and P2Y 1 receptors , and shown to act via NO . An increase in ATP release during oxygen exposure may contribute to birth-related pulmonary vasodilation in lambs (Konduri and Mattei, 2002).…”